Mechanistic analysis of the PD-1 blockade combination cancer immunotherapy with BTK inhibitors.

阿卡拉布替尼在体内可以改变CD8+T细胞的代谢模式，但在体外不能。两种BTK抑制剂均可降低CD8+T细胞UPR基因的表达，尤其是Xbp1s。Xbp1s在肿瘤浸润性CD8+T细胞中的表达高于DLN和非肿瘤LNS。此外，肿瘤浸润性CD8+T细胞中Xbp1s的表达与IFNG、Gzmb、Prf1呈负相关。同样，体外实验表明，高表达CD8+T细胞的Xbp1s比野生型的干扰素-γ、颗粒酶B和穿孔素水平更低。通过分析GEO数据集GSE118430，我们发现XBP1 KO CD4+T细胞表现出与T细胞免疫反应相关的几个基因的相对高表达，如IFNG、CCL5、CXCR5等。

Acalabrutinib could change the metabolic patterns of CD8+ T cells in vivo, but failed in vitro. Both BTK inhibitors could reduce UPR genes expression in CD8+ T cells, especially for Xbp1s. The expression of Xbp1s was up-regulated in tumor-infiltrating CD8+ T cells compared with those from DLNs and tumor-free LNs. In addition, the Xbp1s expression showed negative correlation with Ifng, Gzmb and Prf1 in tumor-infiltrating CD8+ T cells. Similarly, in vitro experiments revealed that Xbp1s overexpressed CD8+ T cells had lower levels of interferon-gamma, granzyme B and perforin than wild type. By analyzing the GEO dataset GSE118430, we found that Xbp1 KO CD4+ T cells showed relatively high expression of several genes associated with T cells immune response such as Ifng, Ccl5, Cxcr5, etc.